达格列净通过抑制NLRP3炎性小体缓解糖尿病大鼠肾脏损伤  

Dapagliflozin Attenuates Renal Lesion by Inhibiting NLRP3 Inflammasome in Diabetic Rats

作　　者：宋道飞 张爱洁 周慧敏[3] 胡旭[3] 曾明星[3] 陈丹 陈伟 张静 SONG Daofei;ZHANG Aijie;ZHOU Huimin(Department of Endocrinology,Hubei Provincial Hospital of Integrated Chinese and Western Medicine,Wuhan,430015)

机构地区：[1]湖北省中西医结合医院内分泌科,武汉430015 [2]湖北省中西医结合医院妇产科,武汉430015 [3]湖北中医药大学,武汉430065

出　　处：《中国中西医结合肾病杂志》2024年第4期290-294,I0001,共6页Chinese Journal of Integrated Traditional and Western Nephrology

基　　金：湖北省卫生健康委员会基金面上项目(No.WJ2021M200)。

摘　　要：目的:观察达格列净对2型糖尿病(T2DM)大鼠肾脏损伤的影响及分子机制。方法:应用高脂饮食结合小剂量链脲佐菌素(streptozotocin,STZ)腹腔注射建立T2DM大鼠模型,将成模大鼠随机分为模型组(Model)、二甲双胍组(Met)和达格列净组(DAPA),并设立正常对照组(Control),每组5只。Met组给予每日150 mg/kg灌胃,DAPA组给予每日10 mg/kg灌胃,Control组和Model组予以等体积蒸馏水灌胃,持续治疗6周,每周称重1次,根据体重变化调整给药剂量。于第6周,将各组大鼠放代谢笼中,检测24 h尿量、24 h尿白蛋白总量(UTP)、尿白蛋白/尿肌酐比值(ACR)。6周末处死大鼠,检测各组大鼠空腹血糖(FBG)、血清总胆固醇(TC)、三酰甘油(TG);HE、PAS染色观察大鼠肾脏病理变化;免疫组织化学法观察大鼠肾组织核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎症小体及相关组分蛋白的表达;Western blot检测肾脏NLRP3炎症小体及相关组分蛋白表达。结果:与Control组比较,Model组大鼠FBG、TC、TG升高(P<0.01),肾脏病理切片出现肾小球体积增大和系膜基质增生等病理改变;与Model组比较,Met组大鼠FBG、TC、TG水平及NLRP3、IL-1β和IL-18蛋白表达降低(P<0.05,P<0.01),ACR、UTP水平及caspase1蛋白表达虽也降低,但差异无统计学意义(P>0.05);DAPA组大鼠FBG、TC、TG、ACR、UTP水平及NLRP3、caspase-1、IL-1β和IL-18蛋白表达降低(P<0.05,P<0.01),肾脏病理变化改善。结论:达格列净通过抑制NLRP3炎症小体,显著降低下游炎性因子水平,从而发挥肾脏保护作用。Objective:To investigate the effect of dapagliflozin on renal injury in diabetic rats and its molecular mechanism.Methods:Diabetic rat model was established by high fat diet combined with intraperitoneal injection of small dose streptozotocin(STZ).The diabetic model rats were randomly divided into control group,model group,metformin(Met)group and dapagliflozin(DAPA)group.The rats in the Met group and DAPA group were given intragastric administration of Met(150 mg/kg per day)and DAPA(10 mg/kg per day)respectively,while the rats in the control group and model group were given equal volume of distilled water,once a day for 6 weeks.The rats were weighed once a week to adjust the dosage according to the change of body weight.After medication for 6 weeks,fasting blood glucose(FBG),serum triglyceride(TG),serum total cholesterol(TC),24 h urinary albumin(UTP)and urinary albumin/creatinine ratio(ACR)were measured.Hematoxylin eosin(HE)staining,as well as periodic acid-schiff(PAS)staining and Masson's trichrome staining(Masson)was used to detect the pathological changes of renal tissue.The protein expression of NLRP3,caspase1,IL-1βand IL-18 in renal tissue of rats in each group was detected by Western blot and immunohistochemistry.Results:There were significant differences in FBG,TG,TC,UTP,ACR and SGLT2 protein expression levels between model group and control group(P<0.01),and the pathological changes of model group were significant.Compared with the model group,the levels of TC,TG,ACR,FBG and UTP in the rats of DAPA group decreased,the protein expression of NLRP3,caspase-1,IL-1βand IL-18 in renal tissues were decreased(P<0.05,P<0.01);the levels of TC,TG and FBG in the rats of Met group decreased,the protein expression of NLRP3,IL-1βand IL-18 in renal tissues were also decreased(P<0.05,P<0.01).Met and DAPA treatment improved renal pathological changes in diabetic rats.Conclusion:Dapagliflozin can exert renal protective function by inhibiting NLRP3 inflammasome and its downstream inflammatory factors in diabetic rats.

关 键 词：糖尿病肾病 达格列净 核苷酸结合寡聚化结构域样受体蛋白3 2型糖尿病 

分 类 号：R587.2[医药卫生—内分泌] R692.9[医药卫生—内科学]